Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery

Inadequate target exposure is a major cause of high attrition in drug discovery. Here, we show that a label-free method for quantifying the intracellular bioavailability (Fic) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined Fic in mult...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2017-07, Vol.114 (30), p.E6231-E6239
Main Authors: Mateus, André, Gordon, Laurie J., Wayne, Gareth J., Almqvist, Helena, Axelsson, Hanna, Seashore-Ludlow, Brinton, Treyer, Andrea, Matsson, Pär, Lundbäck, Thomas, West, Andy, Hann, Michael M., Artursson, Per
Format: Article
Language:English
Subjects:
Amyloid Precursor Protein Secretases - antagonists & inhibitors
Aspartic Acid Endopeptidases - antagonists & inhibitors
Bioavailability
Biological Availability
Biological Sciences
Biological Transport
Cancer
Cells
Compartments
Dementia disorders
Drug discovery
Drug Discovery - methods
drug exposure
Exposure
HEK293 Cells
HL-60 Cells
Humans
Intracellular
intracellular drug bioavailability
MAPK14
Medicin och hälsovetenskap
Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors
Molecules
Pharmacology
PNAS Plus
Protease Inhibitors - pharmacokinetics
Protein Kinase Inhibitors - pharmacokinetics
published kinase inhibitor set
R&D
Research & development
target engagement
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Summary:Inadequate target exposure is a major cause of high attrition in drug discovery. Here, we show that a label-free method for quantifying the intracellular bioavailability (Fic) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined Fic in multiple cellular assays and cell types representing different targets from a number of therapeutic areas, including cancer, inflammation, and dementia. Both cytosolic targets and targets localized in subcellular compartments were investigated. Fic gives insights on membrane-permeable compounds in terms of cellular potency and intracellular target engagement, compared with biochemical potency measurements alone. Knowledge of the amount of drug that is locally available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1701848114